Genetic susceptibility to juvenile idiopathic arthritis in the Belarusian population: gene-gene interactions analysis

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Abstract

Background. GWASs revealed a huge amount of candidate genes for juvenile idiopathic arthritis (JIA) susceptibility. Individual SNP analysis has restrictions as an effect of each substitution may be too subtle to be detected but their interactions may significantly contribute to disease susceptibility.

Materials and methods. 118 patients diagnosed with JIA and 202 controls were included into the study. The study was aimed to estimate interactions between SNPs of the immune and inflammatory responses genes: RUNX3 (rs11249215), RUNX1 (rs9979383), STAT4 (rs7574865), TRAF1/C5 (rs3761847), MIF (rs755622), CTLA4 (rs5742909, rs231775), PTPN2 (rs2542151) and to reveal their effects on the JIA susceptibility. SNPs were genotyped using PCR-RFLP and Real-time PCR. Multifactor dimensionality reduction analysis was performed using MDR 3.0.2 software.

Results. RUNX3, STAT4 and PTPN2 polymorphisms were associated with systemic arthritis, RF- polyarthritis and oligoarthritis respectively. Interaction of CTLA4 (rs5742909, rs231775), TRAF1/C5 (rs3761847), RUNX1 (rs9979383), PTPN2 (rs2542151) SNPs is shown to be a risk factor for JIA (p = 0.0099).

Conclusion. Some of the SNPs studied are associated with distinct JIA subtypes. MDR analysis identified a statistically significant high-order interaction of five polymorphisms which collectively may contribute to JIA genetic susceptibility in the Belarusian population.

About the authors

Hanna A. Yatskiu

Institute of Genetics and Cytology of the National Academy of Sciences of Belarus

Author for correspondence.
Email: a-yackiv@yandex.ru
SPIN-code: 2331-6000

Junior researcher, Laboratory of Molecular Basis of Genomic Stability

Belarus, 220072, Minsk, Akademicheskaya Str. 27

Nataliya V. Savina

Institute of Genetics and Cytology ot the National Academy of Sciences of Belarus

Email: n.savina@igc.by
Scopus Author ID: 7004556893

Researcher, Laboratory of Molecular Basis of Genomic Stability

Belarus, 220072, Minsk, Akademicheskaya Str. 27

Nataliya V. Nikitchenko

Institute of Genetics and Cytology ot the National Academy of Sciences of Belarus

Email: n.nikitchenko@igc.by
Scopus Author ID: 6602842335

Researcher, Laboratory of Molecular Basis of Genomic Stability

Belarus, 220072, Minsk, Akademicheskaya Str. 27

Tatyana D. Kuzhir

Institute of Genetics and Cytology ot the National Academy of Sciences of Belarus

Email: t.kuzhir@igc.by
Scopus Author ID: 6602670470

Doctor of Science, Main Researcher, Laboratory of Molecular Basis of Genomic Stability

Belarus, 220072, Minsk, Akademicheskaya Str. 27

Alexei M. Tchitchko

Belarusian State Medical University

Email: childill1@bsmu.by

PhD, Assistant Professor

Belarus, 220116, Minsk, Dzerzhinski Ave. 83

Alexander V. Sukalo

Belarusian State Medical University

Email: childill1@bsmu.by
Scopus Author ID: 57190016687

Academician, Doctor of Science, Professor, Head of the Department.

Belarus, 220116, Minsk, Dzerzhinski Ave. 83

Roza I. Goncharova

Institute of Genetics and Cytology ot the National Academy of Sciences of Belarus

Email: r.goncharova@igc.by
Scopus Author ID: 6701368733

Doctor of Science, Professor, Head of the Laboratory of Molecular Basis of Genomic Stability.

Belarus, 220072, Minsk, Akademicheskaya Str. 27

References

  1. Fujikawa S, Okuni M. A nationwide surveillance study of rheumatic diseases among Japanese children. Acta Paediatr Jpn. 1997;39(2):242-244. https://doi.org/10.1111/j.1442-200x.1997.tb03592.x
  2. Moe N, Rygg M. Epidemiology of juvenile chronic arthritis in northern Norway: a ten-year retrospective study. Clin Exp Rheumatol. 1998;16(1):99-101.
  3. Prahalad S, Glass DN. Is juvenile rheumatoid arthritis/juvenile idiopathic arthritis different from rheumatoid arthritis? Arthritis Research Therapy. 2002;4(3): 303-310. https://doi.org/10.1186/ar594.
  4. Hinks A, Cobb J, Marion MC, et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet. 2013;45(6):664-669. https://doi.org/10.1038/ng.2614.
  5. Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet. 2011;88(1):76-82. https://doi.org/10.1016/j.ajhg.2010.11.011.
  6. Vermeulen SH, Den Heijer M, Sham P, Knight J. Application of multi-locus analytical methods to identify interacting loci in case-control studies. Ann Hum Genet. 2007;71(Pt 5):689-700. https://doi.org/10.1111/j.1469-1809.2007.00360.x.
  7. Савина Н.В., Яцкив А.А., Никитченко Н.В., и др. Полиморфизм ряда генов иммунного и воспалительного ответа как фактор предрасположенности к ювенильному идиопатическому артриту // Молекулярная и прикладная генетика. – 2018. – Т. 24. – С. 22–36. [Savina NV, Yatskiu HA, Nikitchenko NV, et al. Polymorphism of a set of genes involeved in immune and inflammatory responses as a predisposing factor for juvenile idiopathic arthritis. Molekulzrnaya i prikladnaya genetika. 2018;24: 22-36. (In Russ.)]
  8. Saurenmann RK, Rose JB, Tyrrell P, et al. Epidemiology of juvenile idiopathic arthritis in a multiethnic cohort: ethnicity as a risk factor. Arthritis Rheum. 2007;56(6): 1974-1984. https://doi.org/10.1002/art.22709.
  9. Petty RE, Southwood TR, Manners P, et al. International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2): 390-392.
  10. Cattalini M, Soliani M, Caparello MC, Cimaz R. Sex differences in pediatric rheumatology. Clin Rev Allergy Immunol. 2019;56(3):293-307. https://doi.org/ 10.1007/s12016-017-8642-3.
  11. Салугина С.О. Функциональный статус и качество жизни взрослых больных ювенильным артритом при длительном течении заболевания // Современная ревматология. – 2011. – Т. 5. – № 1. – С. 33–39. [Salugina SO. Functional status and quality of life in adult patients with juvenile arthritis during the long-term course of disease. Sovremennaya revmatologiya. 2011;5(1):33-39. (In Russ.)]
  12. Lotem J, Levanon D, Negreanu V, et al. Runx3 in immunity, inflammation and cancer. Adv Exp Med Biol. 2017;962:369-393. https://doi.org/10.1007/978-981-10-3233-2_23.
  13. Wong WF, Kurokawa M, Satake M, Kohu K. Down-regulation of Runx1 expression by TCR signal involves an autoregulatory mechanism and contributes to IL-2 production. J Biol Chem. 2011;286(13):11110-11118. https://doi.org/10.1074/jbc.M110.166694.
  14. West MJ, Farrell PJ. Roles of RUNX in B cell immortalisation. Adv Exp Med Biol. 2017;962:283-298. https://doi.org/10.1007/978-981-10-3233-2_18.
  15. Hsu FC, Shapiro MJ, Dash B, et al. An essential role for the transcription factor Runx1 in T cell maturation. Sci Rep. 2016;6:23533. https://doi.org/10.1038/srep23533.
  16. Yano F, Hojo H, Ohba S, et al. A novel disease-modifying osteoarthritis drug candidate targeting Runx1. Ann Rheum Dis. 2013;72(5):748-753. https://doi.org/10.1136/annrheumdis-2012-201745.
  17. Авдеева А.С., Александрова Е.Н., Насонов Е.Л. Клиническое значение матриксных металлопротеиназ при ревматоидном артрите (обзор литературы и собственные данные) // Научно-практическая ревматология. – 2014. – Т. 52. – № 1. – С 79–84. [Avdeeva AS, Aleksandrova EN, Nasonov EL. The clinical significance of matrix metalloproteinases in rheumatoid arthritis patients (review of the literature and our own data). Science-practical rheumatology. 2014;52(1):79-84. (In Russ.)]. https://doi.org/10.14412/1995-4484-2014-79-84.
  18. Vecellio M, Roberts AR, Cohen CJ, et al. The genetic association of RUNX3 with ankylosing spondylitis can be explained by allele-specific effects on IRF4 recruitment that alter gene expression. Ann Rheum Dis. 2016;75(8):1534-1540. https://doi.org/10.1136/annrheumdis-2015-207490.
  19. Tsoi LC, Spain SL, Knight J, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012;44(12): 1341-1348. https://doi.org/10.1038/ng.2467.
  20. Eyre S, Bowes J, Diogo D, et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012;44(12):1336-1340. https://doi.org/10.1038/ng.2462.
  21. Steel KJ, Hinks A, Barton A, et al. OP0050 Fine mapping and expression of a locus overlapping 3 Types of inflammatory arthritis. Ann Rheum Dis. 2013;72(3): А66-А67. https://doi.org/10.1136/annrheumdis-2013- eular.255.
  22. Hinks A, Eyre S, Ke X, et al. Overlap of disease susceptibility loci for rheumatoid arthritis and juvenile idiopathic arthritis. Ann Rheum Dis. 2010;69(6): 1049-1053. https://doi.org/10.1136/ard.2009.110650.
  23. Frucht DM, Aringer M, Galon J, et al. Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation. J Immunol. 2000;164(9):4659-4664. https://doi.org/10.4049/jimmunol.164.9.4659.
  24. Lamana A, Balsa A, Rueda B, et al. The TT genotype of the STAT4 rs7574865 polymorphism is associated with high disease activity and disability in patients with early arthritis. PLoS One. 2012;7(8): e43661. https://doi.org/10.1371/journal.pone.0043661.
  25. Lamana A, López-Santalla M, Castillo-González R, et al. The minor allele of rs7574865 in the STAT4 gene is associated with increased mRNA and protein expression. PLoS One. 2015;10(11): e0142683. https://doi.org/10.1371/journal.pone.0142683.
  26. Denkinger CM, Metz C, Fingerle-Rowson G, et al. Macrophage migration inhibitory factor and its role in autoimmune diseases. Arch Immunol Ther Exp (Warsz). 2004;52(6):389-400.
  27. Llamas-Covarrubias MA, Valle Y, Bucala R, et al. Macrophage migration inhibitory factor (MIF): genetic evidence for participation in early onset and early stage rheumatoid arthritis. Cytokine. 2013;61(3): 759-765. https://doi.org/10.1016/j.cyto.2012.12. 032.
  28. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459-465. https://doi.org/10.1084/jem.182.2.459.
  29. Yanagawa T, Hidaka Y, Guimaraes V, et al. CTLA-4 gene polymorphism associated with Graves’ disease in a Caucasian population. J Clin Endocrinol Metab. 1995;80(1):41-55. https://doi.org/10.1210/jcem.80.1.7829637.
  30. Awata T, Kurihara S, Iitaka M, et al. Association of CTLA-4 gene A-G polymorphism (IDDM12 locus) with acute-onset and insulin-depleted IDDM as well as autoimmune thyroid disease (Graves’ disease and Hashimoto’s thyroiditis) in the Japanese population. Diabetes. 1998;47(1): 128-129. https://doi.org/10.2337/diab.47.1.128.
  31. Krokowski M, Bodalski J, Bratek A, et al. CTLA-4 gene polymorphism is associated with predisposition to IDDM in a population from central Poland. Diabetes Metab. 1998;24(3):241-243.
  32. Ligers A, Xu C, Saarinen S, et al. The CTLA-4 gene is associated with multiple sclerosis. J Neuroimmunol. 1999;97(1-2):182-190. https://doi.org/10.1016/ S0165-5728(99)00072-7.
  33. Kemp EH, Ajjan RA, Waterman EA, et al. Analysis of a microsatellite polymorphism of the cytotoxic T-lymphocyte antigen-4 gene in patients with vitiligo. Br J Dermatol. 1999;140(1):73-78. https://doi.org/10.1046/j.1365-2133.1999.02610.x.
  34. Gonzalez-Escribano MF, Rodriguez R, Valenzuela A, et al. CTLA4 polymorphisms in Spanish patients with rheumatoid arthritis. Tissue Antigens. 1999;53(3):296-300. https://doi.org/10.1034/j.1399-0039.1999.530311.x.
  35. Bek S, Bojesen AB, Nielsen JV, et al. Systematic review and meta-analysis: pharmacogenetics of anti-TNF treatment response in rheumatoid arthritis. Pharmacogenomics J. 2017;17(5):403-411. https://doi.org/10.1038/tpj.2017.26.
  36. Rickert RC, Jellusova J, Miletic AV. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev. 2011;244(1): 115-133. https://doi.org/10.1111/j.1600-065X.2011. 01067.x.
  37. Yang S, Wang Y, Mei K, et al. Tumor necrosis factor receptor 2 (TNFR2)·interleukin-17 receptor D (IL-17RD) heteromerization reveals a novel mechanism for NF-κB activation. J Biol Chem. 2015;290(2):861-871. https://doi.org/10.1074/jbc.M114.586560.
  38. Borghi A, Verstrepen L, Beyaert R. TRAF2 multitasking in TNF receptor-induced signaling to NF-κB, MAP kinases and cell death. Biochem Pharmacol. 2016;116: 1-10. https://doi.org/10.1016/j.bcp.2016.03.009.
  39. Plenge RM, Seielstad M, Padyukov L, et al. TRAF1-C5 as a risk locus for rheumatoid arthritis – a genomewide study. N Engl J Med. 2007;357(12): 1199-1209. https://doi.org/10.1056/NEJMoa073491.
  40. Zhu J, Zhang D, Wu F, et al. Single nucleotide polymorphisms at the TRAF1/C5 locus are associated with rheumatoid arthritis in a Han Chinese population. BMC Med Genet. 2011;12:53. https://doi.org/10.1186/1471-2350-12-53.
  41. Sharp RC, Abdulrahim M, Naser ES, Naser SA. Genetic variations of PTPN2 and PTPN22: role in the pathogenesis of type 1 diabetes and Crohn’s disease. Front Cell Infect Microbiol. 2015;5:95. https://doi.org/10.3389/fcimb.2015.00095.
  42. Chistiakov DA, Chistiakova EI. T-cell protein tyrosine phosphatase: a role in inflammation and autoimmunity. Int J Diabetes Mellit. 2010;2(2):114-118. https://doi.org/10.1016/j.ijdm.2010.05.012.
  43. Ellis JA, Scurrah KJ, Li YR, et al. Epistasis amongst PTPN2 and genes of the vitamin D pathway contributes to risk of juvenile idiopathic arthritis. J Steroid Biochem Mol Biol. 2015;145:113-120. https://doi.org/10.1016/j.jsbmb.2014.10.012.
  44. Huang CH, Cong L, Xie J, et al. Rheumatoid arthritis-associated gene-gene interaction network for rheumatoid arthritis candidate genes. BMC Proc. 2009;3 Suppl 7: S75. https://doi.org/10.1186/1753-6561-3-S7- S75.
  45. Jung J, Song JJ, Kwon D. Allelic based gene-gene interactions in rheumatoid arthritis. BMC Proc. 2009;3 Suppl 7: S76. https://doi.org/10.1186/1753-6561-3-S7-S76.

Supplementary files

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2. Fig. 1. The columns show the patients with different JIA subtypes percentagewise

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3. Fig. 2. Polymorphic loci and their contribution to disease susceptibility, measured as entropy in % are shown in the rectangles. Entropy values that characterize paired loci interactions are depicted on lines, connecting the respective rectangles

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Copyright (c) 2019 Yatskiu H.A., Savina N.V., Nikitchenko N.V., Kuzhir T.D., Tchitchko A.M., Sukalo A.V., Goncharova R.I.

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This work is licensed under a Creative Commons Attribution 4.0 International License.
 


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